{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,1,16]],"date-time":"2026-01-16T00:53:01Z","timestamp":1768524781889,"version":"3.49.0"},"posted":{"date-parts":[[2025,7,12]]},"group-title":"Genomics","reference-count":54,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2025,7,12]],"date-time":"2025-07-12T00:00:00Z","timestamp":1752278400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/publicdomain\/zero\/1.0\/"}],"funder":[{"name":"the National Institute on Aging of the National Institutes of Health","award":["U19AG063893"],"award-info":[{"award-number":["U19AG063893"]}]},{"name":"the National Institute on Aging of the National Institutes of Health","award":["U01-AG023746"],"award-info":[{"award-number":["U01-AG023746"]}]},{"name":"the National Institute on Aging of the National Institutes of Health","award":["U01-AG023712"],"award-info":[{"award-number":["U01-AG023712"]}]},{"name":"the National Institute on Aging of the National Institutes of Health","award":["U01-AG023749"],"award-info":[{"award-number":["U01-AG023749"]}]},{"name":"the National Institute on Aging of the National Institutes of Health","award":["U01-AG023755"],"award-info":[{"award-number":["U01-AG023755"]}]},{"name":"the National Institute on Aging of the National Institutes of Health","award":["U01-AG023744"],"award-info":[{"award-number":["U01-AG023744"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2025,7,11]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>\n                  The Trail Making Test (TMT) Part B (TMT-B), a well-established assessment of cognitive function, is a frequent component of diagnostic assessments for Mild Cognitive Impairment and dementia in older adults. Identifying the genetic variants associated with the TMT-B will not only gain insights of genetic determinants of cognitive function, but also the molecular mechanisms for dementia. Published GWAS to date for TMT-B suffer from relatively low power due to the use of population level data and imputation methods. To address these deficits, we used a family-based study design to identify the genetic variants associated with the TMT-B incorporating both genome-wide linkage analysis (GWLS) and whole genome sequencing (WGS). As such, we examined the sequenced genetic determinants of TMT-B using GWLS in over 2000 participants from Long Life Family Study (LLFS). In GWLS, the estimated heritability of TMT-B was 0.29. We detected one significant linkage peak at 15q25 (LOD&gt;3.0). Statistical fine-mapping nominated five variants including three SNPs (\n                  <jats:italic>NTRK3<\/jats:italic>\n                  -rs74031103, protective\n                  <jats:italic>CEMIP<\/jats:italic>\n                  -rs2271159, and protective\n                  <jats:italic>AGBL1<\/jats:italic>\n                  -rs4134376) and two INDELs (protective\n                  <jats:italic>KLHL25<\/jats:italic>\n                  -15:85882445:IND, and protective\n                  <jats:italic>CEMIP<\/jats:italic>\n                  -15:80893381:IND) contributing to the linkage peak. Four out of these five variants are protective for TMT-B. The rs2271159 SNP influences\n                  <jats:italic>CEMIP<\/jats:italic>\n                  expression in cerebellum and hippocampus, while the 15:80893381:IND modulates\n                  <jats:italic>CEMIP<\/jats:italic>\n                  expression in blood. Additionally, the variant rs4134376 is a basal ganglia-specific eQTL for\n                  <jats:italic>AGBL1<\/jats:italic>\n                  . In conclusion, we utilized GWLS, leveraged multi-omics data (whole genome sequence genomic data, transcriptomic data, and lipidomic data), and identified novel protective variants and genes for TMT-B performance.\n                <\/jats:p>","DOI":"10.1101\/2025.07.08.663708","type":"posted-content","created":{"date-parts":[[2025,7,12]],"date-time":"2025-07-12T09:10:10Z","timestamp":1752311410000},"source":"Crossref","is-referenced-by-count":0,"title":["Identification of novel protective loci for executive function using the trail making test part B in the Long Life Family Study"],"prefix":"10.64898","author":[{"given":"Lihua","family":"Wang","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Katherine","family":"Tanner","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Stacy L.","family":"Andersen","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Stephanie","family":"Cosentino","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Vaha Akbary","family":"Moghaddam","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"E. 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